Nuclear Medicine and Biology 44 (2017) 78–82

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Nuclear Medicine and Biology
journal homepage: www.elsevier.com/locate/nucmedbio

Differences in accumulation and the transport mechanism of L- and☆
D-methionine in high- and low-grade human glioma cells
Masato Kobayashi a,⁎, Asuka Mizutani b,c, Kodai Nishi d, Syuichi Nakajima e, Naoto Shikano e, Ryuichi Nishii f,
Kazuki Fukuchi b, Keiichi Kawai g,ha

Wellness Promotion Science Center, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japan
Graduate School of Medicine, Division of Health Sciences, Osaka University, Japan
Department of Radiology, Kanazawa University Hospital, Japand
Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japane
Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Japanf
Molecular Imaging Center, National Institute of Radiological Sciences, Japang
School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Japanh
Biomedical Imaging Research Center, University of Fukui, Fukui, Japanbca r t i c l e

i n f oArticle history:
Received 4 April 2016
Received in revised form 8 September 2016
Accepted 8 September 2016
Keywords:
Methionine
Positron emission tomography
GliomaAmino acid transport systema b s t r a c t
Introduction: Although [S-methyl-11C]-labeled L-methionine and D-methionine (11C-L-MET and 11C-D-MET) areuseful radiotracers for positron emission tomography imaging of brain tumors, it is not known whether the accumulation and transport mechanisms underlying uptake of 11C-D-MET and 11C-L-MET are the same. 11C-L-MET is mainly
taken up by the amino acid transport system L. We evaluated accumulation and the transport mechanism of D-MET
in high- and low-grade human glioma cells in vitro.
Methods: The expression of transport system genes in high- (A172 and T98G) and low-grade (SW1088 and Hs683)
glioma cells was quantitatively analyzed. Accumulation of [S-methyl-3H]-L-MET (3H-L-MET) and [S-methyl-3H]-DMET (3H-D-MET) in these cells was compared during 60 min of incubation. The transport mechanism of 3H-L-MET
and 3H-D-MET was investigated by incubating the cells with these compounds and examining the effect of the inhibitors 2-amino-2-norbornane-carboxylic acid or α-(methylamino) isobutyric acid.
Results: Absolute expression levels of system L and system alanine–serine–cysteine (ASC) in high-grade glioma cells
were higher than in low-grade cells. In high-grade glioma cells, expression of system ASC genes was higher than thatof system L genes. 3H-D-MET, which is transported by systems L and ASC, accumulated at higher levels than 3H-L-MET
at all incubation times because 3H-D-MET is more sensitive to system ASC than 3H-L-MET. Conversely, in low-grade
glioma cells with lower expression of system L and ASC, 3H-D-MET accumulated at higher levels than 3H-L-MET inearly incubation times because 3H-D-MET may be more sensitive to system ASC than system L.
Conclusion: 3H-D-MET was mainly transported by systems L and ASC and sensitive to system ASC, whereas 3H-LMET was transported by system L in human glioma cells. In vitro, the accumulation of 3H-D-MET was signiﬁcantly
higher than that of 3H-L-MET during the entire incubation time in high-grade glioma cells, and in early incubation
times in low-grade glioma cells.
© 2016 Elsevier Inc. All rights reserved.

1. Introduction[S-methyl-11C]-L-methionine (11C-L-MET), a natural amino acid, hasbeen used as a positron emission tomography (PET) tracer to detect tumors. 11C-L-MET is transported into cells through the amino acid transport system L and accumulates in tumors due to enhanced protein☆ Financial support: This study was partly funded by Grants-in-Aid for Scientiﬁc Research from the Japan Society for the Promotion of Science (Nos. 26461801, 26860988,
15K09949, and 15K15452).
⁎ Corresponding author at: Wellness Promotion Science Center, College of Medical,
Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa
920-0942, Japan. Tel.: +81 76 265 2500; fax: +81 76 265 2590.
E-mail address: kobayasi@mhs.mp.kanazawa-u.ac.jp (M. Kobayashi).
http://dx.doi.org/10.1016/j.nucmedbio.2016.09.003
0969-8051/© 2016 Elsevier Inc. All rights reserved.

synthesis and the transmethylation metabolic functions of tumors [1].
Although 2-[18F]-ﬂuoro-2-deoxy-D-glucose (18F-FDG) is used most frequently for PET imaging of tumors, 11C-L-MET is superior to 18F-FDG for
diagnosis and follow-up of glioma patients because 11C-L-MET does notaccumulate much in normal brain due to low protein synthesis andtransmethylation metabolic function and because of the high contrast
between gliomas and normal brain compared with 18F-FDG [2,3].
Because [S-methyl-11C]-labeled D-MET (11C-D-MET) is less affectedby enzymatic metabolism than 11C-L-MET and therefore has fewer metabolites [4], 11C-D-MET more closely reﬂects the transport function of
the amino acid transport system L and the alanine–serine–cysteine(ASC) system in tumor cells. 11C-D-MET is clinically superior to 11C-LMET as a PET tracer for imaging of abdominal tumors [4,5]. 11C-L-METM. Kobayashi et al. / Nuclear Medicine and Biology 44 (2017) 78–82

mainly accumulates in gliomas due to protein synthesis [2,3]. However,accumulation and the transport mechanism of 11C-D-MET have notbeen investigated in brain tumor cells. In this in vitro study, we investigated accumulation and the transport mechanism of 11C-D-MET inhigh- and low-grade human glioma cells. Real-time reverse
transcription-polymerase chain reaction (qRT-PCR) was used to measure the expression of neutral amino acid transport system genes. Correlations between brain tumor cell accumulation of 3H-L- and D-MET,
which are the same chemical compounds as 11C-L- and D-MET but
have a longer half-life, and the expression of neutral amino acid transport system genes were evaluated.

79

Table 1
Expression of genes of the neutral amino acid transport systems in human brain tumor
cells.

Na+-dependent

TransportsystemGene
nameHigh-grade

Low-grade

A172

T98G

SW1088 Hs683

A

SNAT1
SNAT2
SNAT4
ASCT1
ASCT2
LAT1
LAT2
LAT3
LAT4
4F2hc

101.86249.002.66
82.96
351.75297.54
3.50
4.86
18.05
475.4897.65
339.750.01
46.22
435.82350.77
1.91
8.45
1.57
477.1754.42
229.044.60
44.86
251.99258.42
14.83
3.89
6.35
393.36ASC
Na+-independent L

2. Material and methods
Coupling
factor

2.1. Materials

88.68
200.873.59
26.50
106.60172.98
2.62
2.62
14.57
267.88

Data are expressed as copy number per 1000 copies of housekeeping genes.

[S-methyl-3H]-L-MET (3H-L-MET: 2.96 GBq/mmol) and [S-methyl3H]-D-MET ( 3H-D-MET: 2.96 GBq/mmol) were purchased from
American Radiolabeled Chemicals Co. (St Louis, MO, USA). Because
11
C-L-MET and 11C-D-MET have a short half-life, and the tritiated compounds function similarly as 11C-labeled compounds, we used 3H-LMET and 3H-D-MET instead of 11C-L-MET and 11C-D-MET.
2.2. Tumor cells
The following cultured human glioma cell lines were purchasedfrom American Type Culture Collection (Manassas, VA, USA): highgrade glioblastoma (A172 and T98G) [6], low-grade astrocytoma(SW1088), and low-grade oligodendroglioma (Hs683) [7]. All glioma
cells (2.0 × 10 5 cells/mL/well) were incubated in 24-well plates inDulbecco's Modiﬁed Eagle's Medium (Wako, Osaka, Japan) for A172
and Hs683 cells, Eagle's minimal essential medium (Wako) for T98G
cells, and L-15 medium for SW1088 cells. All media were supplemented
with 10% fetal bovine serum, 100 U/mL penicillin, and 0.1 mg/mL streptomycin. Cells were grown at 37 °C in air (SW1088) or a 5% CO2 atmosphere (A172, T98G, and Hs683). A cell proliferation curve wasprepared to determine the duration of the logarithmic growth phase.
2.3. The expression of amino acid transporter in human glioma cells
The expression of amino acid transporters in human glioma cells
was investigated according to our previous study [4]. In brief, total
RNA was harvested from each glioma cell line using an RNeasy Minikit (QIAGEN K. K, Tokyo, Japan). cDNA was synthesized only fromhigh-quality total RNA using an AfﬁnityScript qRT-PCR cDNA Synthesis
kit (Agilent Technologies) by incubating the reaction for 5 min at
25 °C, 15 min at 42 °C, and 55 min at 95 °C. The genes analyzed with
qRT-PCR using an Mx3005P thermocycler (Agilent Technologies) aresummarized in Table 1. Ampliﬁcation was performed for 2 min at
95 °C for one cycle; 5 s at 95 °C followed by 20 s at 60 °C for 40 cycles;
1 min at 95 °C followed by 30 s at 55 °C and 30 s at 95 °C for one
cycle. The expression levels of neutral amino acid transport systemgenes in each cell line were calculated using a calibration curve foreach gene. These experiments were all performed in triplicate.

inhibition assay, the cells were incubated for 5 min with 3H-L-MET
or 3H-D-MET plus 1.0 mM inhibitor: 2-amino-2-norbornane-carboxylic
acid (BCH; Sigma Chemical Co.), a substrate speciﬁc to system L transporters, or α-(methylamino) isobutyric acid (MeAIB; Sigma ChemicalCo.), a substrate speciﬁc to system A transporters. At the end of the incubation, each well was rapidly washed twice with ice-cold incubation
medium. The cells were then solubilized in 0.5 mL 0.1 N NaOH mixed
with Ultima Gold™ Scintillation Cocktail (PerkinElmer, Waltham, MA,
USA), and radioactivity was then measured with a liquid scintillation
counter (Aloka, Tokyo, Japan; LSC-5100). These experiments were all
performed in quadruplicate.
The contribution of amino acid transport systems to MET transport
was evaluated according to our previous study [4]. Brieﬂy, MET accumulation in the absence of inhibitors was considered as a percentage of thecontrol value, which was set at 100%. System A transport was calculated
by subtracting MET accumulation in the presence of MeAIB from accumulation in control Na+-PBS. System ASC transport was calculated bysubtracting the value of MET accumulation in control Na +-free PBS
from MET accumulation in the presence of MeAIB. Finally, system L
transport was calculated by subtracting MET accumulation in the presence of BCH from MET accumulation in control Na +-free PBS. The rates
of tumor cell accumulation of 3H-L-MET and 3H-D-MET were calculated
as % injected dose/100 μg protein. The correlation between tumor cell
accumulation of 3H-L-MET and 3H-D-MET and expression of neutralamino acid transport system genes was also examined. These measurements were performed in quadruplicate.
2.5. Statistical analysis
Data are presented as means and standard deviation (SD). P values
were calculated using a two-tailed paired Student's t test for comparison between two groups. A P value less than 0.05 was consideredsigniﬁcant.
3. Results
3.1. Expression of amino acid transport system genes in human glioma cells

2.4. Assay of MET transport in human glioma cells
Transport assays were performed according to the method described by Shikano et al. [8]. In brief, the sodium-containing incubation
medium used was based on phosphate-buffered saline (Na +-PBS),
whereas in the sodium-free incubation medium (Na +-free PBS), NaCl
and Na2HPO4 were replaced with the equivalent concentrations of choline chloride and K2HPO4, respectively. After pre-incubation with incubation medium for 10 min, the cells were incubated with 0.5 mL
incubation medium containing 3H-L-MET or 3H-D-MET (18.5 kBq) for
2, 5, 10, 15, 30, or 60 min at 37 °C as a control. For the competitive

The high quality of the total RNA harvested from each glioma cellline was conﬁrmed using a bioanalyzer (data not shown). In Table 1,genes for transporters of the Na+-dependent transport systems, system
A and system ASC, were highly expressed in T98G, followed by A172,
SW1088, and Hs683 cells. Genes for transporters of the Na +independent transport system, LAT1, and the coupling factor, 4F2hc,
were also highly expressed in T98G and A172 cells, followed by
SW1088, and then Hs683 cells. The expression levels of ASCT2 werehigher than those of LAT1 and SNAT2 in high-grade cells, and those of
ASCT2 levels were similar to those of LAT1 in low-grade cells.

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M. Kobayashi et al. / Nuclear Medicine and Biology 44 (2017) 78–82

B
20
15

**

* *

*

*

10
5
0

0

10

20

30

40

50

60

Accumulation(%injected dose/100 g protein)

Accumulation(%injected dose/100 g protein)

A

15
10

*

*

* *

*

*

5
0

0

10

20

30

40

50

60

Time (min)Time (min)

D
20
15

*

** * *

10
5
0

0

10

20

30

40

50

60

Time (min)Accumulation(%injected dose/100 g protein)C
Accumulation(%injected dose/100 g protein)

20

20
15
10

*

* * *

**

**

5
0

0

10

20

30

40

50

60

Time (min)Fig. 1. The contribution of 3H-L-MET (●) and 3H-D-MET (■) in A172 (A), T98G (B), SW1088 (C), and Hs683 (D) cells. 3H-D-MET accumulation was higher than 3H-L-MET accumulation in
the high-grade glioma cells, A172 (A) and T98G (B), throughout the entire incubation time, whereas in the low-grade glioma cells, SW1088 (C) and Hs683 (D), 3H-D-MET showed higher
accumulation than 3H-L-MET during early incubation times, then 3H-L-MET accumulation gradually increased and became higher than 3H-D-MET at 60 min of incubation. The asterisks
and double asterisks indicate P b 0.01 and P b 0.05, respectively, between the accumulation of 3H-L-MET and 3H-D-MET in each tumor cell line.

3.2. Assay of MET transport in human glioma cells
Accumulation of 3H-L-MET and 3H-D-MET was investigated inhuman glioma cells for 60 min (Fig. 1). For both tracers, the area
under the radioactivity curve in high-grade glioma cells was higher
than that in low-grade glioma cells. In the high-grade glioma cell lines,
A172 and T98G, accumulation of 3H-D-MET was signiﬁcantly higher
than that of 3H-L-MET throughout the entire incubation time. In the
low-grade glioma cells, SW1088 and Hs683, accumulation of 3H-LMET was signiﬁcantly lower than that of 3H-D-MET during the early incubation times and then became higher than 3H-D-MET after 60 min of
incubation.
3.3. The contribution of each amino acid transport system for accumulationof MET in human glioma cells
The contribution of each amino acid transport system to tumor cell
accumulation of 3H-L-MET and 3H-D-MET was analyzed using speciﬁc

A

Accumulation (% of control)

100

80

60

40

20

inhibitors and was measured at 5 min after 3H-L-MET or 3H-D-MET incubation (Fig. 2). For accumulation of 3H-L-MET in all cell lines, system L
was mainly involved and mediated over 65% of the total accumulationof 3H-L-MET in control conditions. For accumulation of 3H-D-MET, system L mediated over 54% of the total 3H-D-MET accumulation in each of
the tumor cell lines in control conditions. We observed involvement of
not only system L but also system A and/or system ASC. System ASC
was more involved in the low-grade glioma cell lines, SW1088 andHs683, than the high-grade glioma cell lines, A172 and T98G. Involvement of system A was relatively lower than that of systems L and ASC
in both 3H-L-MET and 3H-D-MET accumulation.
3.4. Correlation between MET accumulation and transporter expression inhuman glioma cells
The correlation between tumor accumulation of MET and the expression of amino acid transport system genes is shown in Table 2.
When we evaluated correlations between 3H-L-MET accumulation

B

Accumulation (% of control)

0

20

0
A172

*
*

System L

*

40

80

100

**

T98G

**
**

SW1088

**

Hs683

**

System A

60

**
**

System ASC

Fig. 2. Contribution of each amino acid transport system with 3H-L-MET (A) and 3H-D-MET (B) accumulation in human glioma cells at 5 min of incubation. System L was involved in tumor
cell accumulation of 3H-L-MET, whereas both systems L and ASC were involved in tumor cell transport of 3H-D-MET. The asterisks and double asterisks indicate P b 0.01 and P b 0.05,
respectively, between the accumulation of 3H-L-MET and 3H-D-MET in each tumor cell line. These data were calculated using inhibitors as shown in Fig. 1.

M. Kobayashi et al. / Nuclear Medicine and Biology 44 (2017) 78–82
Table 2
Correlation coefﬁcients (R2) between tumor uptake of 3H-L-MET and 3H-D-MET at 5 min of
incubation and the expression of amino acid transport system genes in human brain tumor cells.
Correlation between MET and gene expression

L
L+A
L + ASC
L + ASC + A

3H-L-MET

3H-D-MET

0.90
0.74
0.86
0.87

0.81
0.88
0.97
0.91

and expression of system L genes, and between 3H-D-MET accumulation and expression of both systems L and ASC genes in glioma cells,
the highest correlation was found between both 3H-L-MET accumulation and system L (R 2 = 0.90), and 3H-D-MET accumulation and systems L and ASC genes (R2 = 0.97) (Fig. 3).
4. Discussion
In this in vitro study, we investigated accumulation and the transport mechanism of 3H-L-MET and 3H-D-MET into high- and low-grade
human glioma cells in comparison with qRT-PCR evaluation of the expression levels of neutral amino acid transport system genes in the glioma cells. In our previous study of three different human cancer celllines—lung, breast, and colon cancer cells— 3H-L-MET was mainlytransported via system L, and 3H-D-MET was mainly transported via
systems L and ASC [4].
Our current in vitro study basically shows just transport function
and not metabolism of L- and D-MET. In Fig. 1, signiﬁcantly higher accumulation of 3H-D-MET than 3H-L-MET was seen in the high-grade glioma cell lines, A172 and T98G. Although 3H-D-MET was transported
through systems L, A, and ASC in the A172 and T98G cell lines, the involvement of systems A and ASC was signiﬁcantly higher for 3H-DMET transport (Fig. 2). We previously reported that 3H-D-MET wastransported via systems L and ASC in human abdominal tumor cells[4]; thus, we here examined the correlation between 3H-D-MET accumulation and the expression levels of genes for systems L and ASC in
human glioma cells. 3H-D-MET uptake showed the highest correlation
with systems L and ASC combined (R2 = 0.97, Table 2 and Fig. 3).
Expression levels of system ASC genes (ASCT1, 2) in high-grade glioma cells were higher than those of system L (LAT1–4, Table 1). Therefore, system ASC was responsible for higher accumulation of 3H-DMET than 3H-L-MET in high-grade glioma cells. In the low-grade glioma

Accumulation(%injected dose/100 g protein)Acells, SW1088 and Hs683 (Fig. 1), the accumulation of 3H-D-MET was
higher than that of 3H-L-MET at early incubation times; but 3H-L-MET
accumulated at higher levels than 3H-D-MET at late incubation times.
In Table 1, the expression levels of system L genes (LAT1–4) were nearly
equal to those of system A (SNAT1, 2, 4) and ASC (ASCT1, 2) genes in
SW1088 cells, and were higher than those of system ASC genes(ASCT1, 2) but lower than those of system A genes (SNAT1, 2, 4) in
Hs683 cells. Therefore, the involvement of systems ASC and/or A
allowed 3H-D-MET accumulation at higher levels than 3H-L-MET in glioma cells, whereas system L may cause signiﬁcant 3H-L-MET accumulation in glioma cells (Figs. 1 and 2). If there is also higher in vivo
expression of system ASC in high-grade gliomas than in low-grade gliomas, 11C-D-MET may accumulate more in the high-grade gliomas andmay provide brain images with high contrast because of its high metabolic stability. Although 11C-D-MET may be useful for diagnosis andstaging of these gliomas, its usefulness for studies in human patientsneeds to be conﬁrmed. 11C-L-MET is taken up through system L not
only in brain tissue but also in gliomas, and accumulates in gliomas
due to protein synthesis and transmethylation in tumors during
human clinical examination. Therefore, future in vivo results in human
may be different.
In a distribution study with abdominal tumor-bearing mice (n = 4)
injected with 14C-L-MET and 3H-D-MET, the mice were sacriﬁced at 5,
10, 30, and 60 min after MET injection, and the brains were excised[4]. The cerebral accumulation of 3H-L-MET was 1.31 ± 0.18, 1.99 ±
0.28, 1.63 ± 0.17, and 1.30 ± 0.11% injected dose (ID)/g tissue at 5,
10, 30, and 60 min after injection. On the other hand, 3H-D-MET accumulation in the brain was 1.20 ± 0.14, 1.89 ± 0.21, 1.92 ± 0.14, and1.80 ± 0.18%ID/g tissue at 5, 10, 30, and 60 min after injection, respectively. Speciﬁcally, not much difference was observed in normal brain
accumulation between 3H-L-MET and 3H-D-MET during early injection
times as input functions. Therefore, we suggest that accumulation of 3HL-MET and 3H-D-MET in brain tumors in mice may be similar to the accumulation observed in the in vitro study in Fig. 1 because brain tumors
induce the same disruption in the blood–brain barrier in mice whether
injected with 3H-L-MET or 3H-D-MET. Unfortunately, we could not use
glioma-bearing mice to evaluate accumulation of 3H-L-MET and 3H-DMET because injection of our four human-derived glioma cell lines
into normal mouse brain was difﬁcult. An in vivo study of gliomabearing mice or patients with glioma should be performed to determine
if glioma imaging with 11C-D-MET is superior to that of 11C-L-MET, andto investigate glioma diagnosis and staging. In addition, the transportmechanism of both METs in glioma cells could be clariﬁed with anin vitro study.

B
16

R2 = 0.90

12
8
4
0

0

100

200

300

Gene expression (system L)(arb. units)

400

Accumulation(%injected dose/100 g protein)

System81

16

R2 = 0.97

12
8
4
0

0

300

600

900

Gene expression (system L+ASC)(arb. units)

Fig. 3. Correlation between tumor cell accumulation of 3H-L-MET and 3H-D-MET at 5 min of incubation and the expression of amino acid transport system genes in human glioma cell lines,
H172 (●), T98G (▲), SW1088 (■), and Hs683 (○). The graphs show the highest correlation between 3H-L-MET accumulation and expression of system L genes (A), and that between 3HD-MET accumulation and expression of system L and system ASC genes (B).

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M. Kobayashi et al. / Nuclear Medicine and Biology 44 (2017) 78–82

5. Conclusion

Appendix A. Supplementary data

The transport mechanisms of 3H-L-MET and 3H-D-MET differed inhuman glioma cells. 3H-D-MET was mainly transported by systems L
and ASC and more sensitive to system ASC than system L, whereas 3HL-MET was transported by system L. Based on these transportmechanisms in our in vitro study, the accumulation of 3H-D-MET was
signiﬁcantly higher than that of 3H-L-MET throughout the entire incubation time in high-grade glioma cells, and during early incubation
times in low-grade glioma cells.

Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.nucmedbio.2016.09.003.

Conﬂicts of interest
There are no conﬂicts of interest.

Acknowledgments
The authors thank Takahiro Niwa and the other staffs of the School of
Health Sciences, Kanazawa University for their technical support. This
study was partly funded by Grants-in-Aid for Scientiﬁc Research fromthe Japan Society for the Promotion of Science (Nos. 26461801,
26860988, 15K09949, and 15K15452).

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